Androstenedione is a C.sub.19 steroid of the formula: ##STR1##
Androsta-4,9(11)-diene-3,17-dione refers to androstenedione with an additional double bond between carbon atoms 9 and 11. Androsta-4,9(11)-diene-3,17-dione type compounds refer to steroids within the scope of formula II: ##STR2## R.sub.6, R.sub.16 and .about. are defined infra.
The androsta-4,9(11)-diene-3,17-dione type compounds (II) are useful for producing pharmaceuticals, in particular testosterone derivatives. For example, androsta-4,9(11)-diene-3,17-dione (II) is converted to 3-(N-pyrrolidinyl)-androsta-3,5,9(11)-triene-17-one to protect the C.sub.3 ketone by the process disclosed by F. W. Heyl and M. E. Herr in J. Am. Chem. Soc. 77, 488 (1955). This protected steroid is converted to 17.beta.-hydroxy-17.alpha.-methylandrosta-4,9(11)-dien-3-one by a Grignard reaction with methyl magnesium bromide and subsequent alkaline hydrolysis. See M. E. Herr et al., J. Am. Chem. Soc. 78, 500 (1956). This methyltestosterone derivative is then converted to 9.alpha.-fluoro-11.beta.,17.beta.-dihydroxy-17-methylandrost-4-en-3-one (fluoxymesterone, Halotestin.RTM.) which is a commercially marketed steroid, by the process of U.S. Pat. No. 3,118,880, Example 2.
The .DELTA..sup.9(11) -steroids have been prepared from both 11.beta.-hydroxy steroids and 9.alpha.-hydroxy steroids. George G. Hazen and D. W. Rosenburg, J. Org. Chem. 29, 1930 (1964) and U.S. Pat. No. 3,094,543; D. Taub et al., J. Am. Chem. Soc. 82, 4102 (1970); E. M. Chamberlain, J. Org. Chem. 25, 295 (1960); T. Reichstein, U.S. Patent 2,409,798; Drake, U.S. Patent 3,005,834; and Great Britain Patent No. 1,198,749 all disclose synthesis of .DELTA..sup.9(11) -steroids from 11.beta.-hydroxy steroids. The papers and patents by Hazen, Taub, and Chamberlain all disclose using 11.beta.-hydroxy corticoids to form the corresponding .DELTA..sup.9(11) -corticoids. U.S. Pat. No. 2,409,798 (Example 3), U.S. Pat. No. 3,005,834 (Example 35) and Great Britain Patent No. 1,198,749 (Example 1) disclose the use of 11.beta.-hydroxyandrostenes to produce .DELTA..sup.9(11) -androstenes.
The .DELTA..sup.9(11) -steroids have also been prepared from the corresponding 9.alpha.-hydroxy steroids.
East German Patent No. 20,528 disclosed using p-TSA in dry benzene to dehydrate 9.alpha.-hydroxy steroids of the pregnane series to the corresponding .DELTA..sup.9(11) -pregnanes. C. G. Bergstrom and R. B. Dodson, Chem. and Ind. (London) 1530 (1961), treated 9.alpha.-hydroxyandrostenedione with p-TSA in benzene. Upon workup 9,10-secoandrost-4-ene-3,9,17-trione and 9.alpha.-hydroxy-4-methylestr-4-ene-1,17-dione were identified; there was no androsta-4,9(11)-diene-3,17-dione (II).
C. G. Bergstrom et al. in J. Org. Chem. 28, 2633 (1963) at page 2638 described reacting 2.0 g. of 9.alpha.-hydroxyandrostenedione with hydrogen fluoride pyridine reagent to produce 9.alpha.-fluoroandrostenedione as well as androsta-4,9(11)-diene-3,17-dione.
The present invention requires a non-aromatic oxygenated acid with a pK.sub.a of less than or equal to 1.0. Hydrogen fluoride pyridine reagent is not an oxygenated acid and it has a pK.sub.a of greater than 1.0.
Dehydration of alcohols with acids is well known to those skilled in the art. The acid dehydration of tertiary alcohols is so well known that the mechanism has been worked out. The acid protonates the hydroxyl group. Upon leaving of the protonated hydroxyl group as water, the reactant is left as a carbonium ion. Loss of a proton from the carbonium ion takes place so as to form the thermodynamically most stable olefin. This acid dehydration of tertiary alcohols normally leads to the more substituted alkene and is known as an E.sub.1 -type reaction, see Basic Principles of Organic Chemistry, J. D. Roberts and M. C. Caserio, W. A. Benjamin, Inc., New York, 1964, pp. 313 and 396; and Mechanism and Structure in Organic Chemistry, E. S. Gould, Holt, Reinhart and Winston, New York, 1964, pp. 475 and 480. It is now clear that when two different olefins may result from a tertiary alcohol by an E.sub.1 elimination reaction, the olefin bearing the larger number of alkyl substituents will predominate in the absence of complicating effects. This rule of organic chemistry is so well known that it is termed Saytzeff's Rule, see Gould, supra, p. 481.
Following Saytzeff's Rule acid dehydration of 9.alpha.-hydroxy steroids should yield predominately the corresponding .DELTA..sup.8 -steroid and not the corresponding .DELTA..sup.9(11) -steroid. More particularly, acid dehydration of 9.alpha.-hydroxyandrostenedione (I) should produce predominantly androsta-4,8-diene-3,17-dione and not androsta-4,9(11)-diene-3,17-dione (II).
The process of the present invention dehydrates 9.alpha.-hydroxyandrostenedione-type compounds (I) to the corresponding androsta-4,9(11)-diene-3,17-dione-type compounds (II) in very high yields with a ratio for androsta-4,9(11)-diene-3,17-dione (II) to androsta-4,8-diene-3,17-dione of greater than 98 to 2. This high yield and very high ratio is most surprising and unexpected in view of the prior art methods and the literature descriptions of the method of acid dehydration of tertiary alcohols and is highly advantageous from a commercial point of view.